Adamantanopyrimidine compounds and intermediates therefor

ABSTRACT

ADAMANTANOPYRIMIDINE COMPOUNDS OF THE FORMULAE:   3,11-DI(R-),6-R&#34;,8-R&#39;&#39;,1-R-4,7,8,9-TETRAHYDROADAMANTANO-   (4,3-D)PYRIMIDINE, AND 1,3,11-TRI(R-),5-R&#34;,6-(O=),8-R&#39;&#39;-   PERHYDROADAMANTANO(4,3-D)PYRIMIDINE   USEFUL AS ANALGESICS AND AS LOCAL ANAESTHETICS; AND INTERMEDIATES USEFUL IN THE SYNTHESIS OF THE FOREGOING ADAMANTANOPYRIMIDINE COMPOUNDS.

United States Patent Office 3,746,161

Patented July 17, 1973 R 3,746,761 ADAMANTANOPYRIMIDINE COMPOUNDS AND RR fi Y INTERMEDIATES THEREFOR Jiban Kumar Chakrabarti, Frimley, andStephen Slomo i Szinai, Workingham, England, assignors to Eli Lilly 5 1.4 2 and Company, Indianapolis, Ind. 0 l3 -NH-R" No Drawing. Originalapplication May 1, 1969, Ser. No.

821,063, now Patent No. 3,644,356. Divided and this R application Apr.5, 1971, Ser. No. 131,439 VI. R

Int. Cl. C07c 61/36 7 s\ US. Cl. 260-544 L 2 Claims 6 R A '\-/5IABSTRACT OF THE DISCLOSURE 1 10 2 Adamantanopyrimidine compounds of theformulae:

c--o-cH=- I. R n. R' I R ll 41% mg 411(1) H In the above and succeedingformulae,

\ 1 7 (1) each R represents hydrogen or C -C loweralkyl, the sum of thenumber of carbon atoms in all three R 14 1' 4 6 R M 6 0 groups being notgreater than 6;

4 (2) each R independently represents hydrogen or IL I% straight-chain C-C alkyl;

R g (3) each R" independently represents hydrogen or C -C loweralkyl;useful as analgesics and as local anaesthetics; and inter- Xfepresfillts mediates useful in the synthesis of the foregoing ada o omantanopynnndlne compoun s i J-1mlogen, -NH:, NH-2, Ol' -NH&R"

and CROSS REFERENCE TO RELATED APPLICATION (5) Y Presents Thisapplication is a divisional application of our 00- E E pendingapplication Ser. No. 821,063, filed May 1, 1969 i t now US. Pat.3,644,356.

(6) Z represents SUMMARY OF THE INVENTION 0 O O The present invention isconcerned with the preparation L g 1] of certain adamantanopyrimidinecompounds and With in 40 l i t useful 5 2 2 il f g g g The subjectmatter of the present invention can more i i fi f e u 6 Pro uc s o Presreadily be understood by reference to the following sumen mven are 0 6as mary reaction scheme. In this reaction scheme, as generally herein,the symbol Ad is employed to designate I, 1L a 1,2-divalent adamantylradical of the formula CH CH /10 /8\ 1(\ R 9 TNH gla u 7N1! R- ,1 Y i14. 4 91B" 14- 4 6 =0 10 i 2 \lL/\ R I ll! The intermediates are of theformulae; and the symbol Ad, to designate a 1,2,2-trivalent adamantylradical of the formula III. R IV. R O

/s s l [I i s\ R- 7 -on-x 11* 1 CHNHG-R a 0 \I/u u /o I o 1" Ii 14 1 =01 NH is l 2 Formula I DETAILED DESCRIPTION OF THE INVENTION example, thecompound of Formula II in which all R, R, and R" symbols designatehydrogen:

is named 5,7-diazatetracyclo(7.3.1.1 .0 )tetradecan-6- one.

As is evident from the summary reaction scheme hereinabove, the presentinvention is concerned ultimately with the preparation of compoundswhich can be described generically as adamantanopyrimidine compounds,the compounds of Formulae I and II. However, for the purpose of thefollowing discussion, the various reactions are sub-divided intosections I, II, and III, as indicated hereinabove in the summaryreaction scheme.

SECTION -I In accordance with this section, a 2-keto-1-adamantaneaceticacid:

R 0 /t JHy2-0I a is converted to the corresponding acyl halide:

R 0 (IE-("J-hnlogen a The conversion can be accomplished in any of theknown procedures for conversion of an acid to an acyl halide. Mosttypically, the acid is reacted with a phosphorus halide, preferably,thionyl halide. Excess reagent or typical solvents, such as thehydrocarbons, can be used as an inert liquid reaction medium; thereaction goes forward at temperatures over a wide range, such as fromroom temperature or below to C. or higher. Work-up is carried out inconventional procedures.

The resulting acyl halide is then converted to the corresponding amide:

R o (JH-iJ-NH,

in known procedures for conversion of acids to amides. Thus, the acid isreacted with ammonia, in the form of aqueous ammonia or as gaseous dryammonia. Hoffmann degradation of the resulting amide yields thecorresponding amine:

The keto group of this amine compound is then reductively aminated byreaction with an amine of the formula NI-I R" to obtain thecorresponding Z-amino-l-adamantanemethylamine:

R7 (IE-NH:

\NH-R" Reductive amination is accomplished in accordance with procedureswell known in the prior art for this reaction. Thus in the foregoingprocedure are prepared all of the intermediates of Section I.

SECTION II In accordance with Section II, various procedures areutilized to obtain the ultimate products of the present invention whichare of Formula I.

Initially, a 2-keto-1-adamantanemethylamine (EH-NH:

prepared as discussed in Section I, is acylated by reaction with an acylhalide of the formula i halo--R" to yield the corresponding2-keto-N-acyl-l-adamantanemethylamine:

U /CHNHCR" s This intermediate, in turn, is reductively aminated withammonia, affording the correspondingZ-amino-N-acyl-ladamantanemethylamine:

RI ('JEL-NH-ii-R" \NHQ This intermediate is then cyclized to obtain theultimate products of the present invention which are of Formula I:

Cyclization can be effected by treatment with a base.

Thus, in this method are prepared the various intermediates involved inSection II, as well as the ultimate products of Formula I.

SECTION III In accordance with Section III, various procedures areutilized to obtain the ultimate products which are of Formula H.

These ultimate products of Formula H are prepared by either of twoseparate synthetic routes.

In a first synthetic route the 2-keto-l-adamantaneacetic acid referredto in Section I:

is reductively aminated by an amine of the formula NH -R" to obtain thecorresponding 2-amino-l-adamantaneacetic acid:

The amine moiety thereof is protected, such as by reaction with benzylchloroformate, and the acid group of the resulting compound 3' 0)ur-tl-ou R" 1 protecting group Cyclization is effected by subjectingthe 2-aminoladamantaneacetamide to Hoffmann rearrangement conditions.

Thus in the manners described foregoing are prepared all of the ultimateproducts and intermediates of the present invention.

The ultimate products of the present invention which are of Formula Iare readily reacted with acids in standard procedures to formcorresponding acid addition salts.,

Particularly suited for the practice of the present invention arepharmaceutically acceptable acid addition salts. Such salts include thechloride, bromide, iodide, sulfate, bisulfate, acetate, salicylate,valerate, laurate, benzoate, phosphate, and the like.

The following examples illustrate the present invention and will enablethose skilled in the art to practice the same.

EXAMPLE 1 2-keto-l-adamantaneacetyl chloride 2-keto-l-adamantaneaceticacid (5.0 grams; 0.024 mole) was dissolved in thionyl chloride (25 ml.)and the solution was heated under reflux for 1 hour. Excess thionylchloride was removed under vacuum and the residue was dissolved in drybenzene and again evaporated under vacuum to obtain the desired2-keto-l-adamantaneacetyl chloride as a residue.

EXAMPLE 2 2-keto-l-adamantaneacetamide The 2-keto-l-adamantaneacetylchloride obtained as reported in Example 1 was dissolved in dry ether(50 ml.) and ammonia was passed into the stirred solution for 1 hour atroom temperature. After removal of the ether the residue was partitionedbetween water (50 ml.) and chloroform (50 ml.) and the aqueous phase wasextracted with two further 50 ml. portions of chloroform. The combinedchloroform extract was washed with 10 percent w./v. sodium carbonatesolution (50 ml.), then with two 50 ml. portions of water, dried overmagnesium sulfate and evaporated to give the expected 2-keto-1-adamantaneacetamide product as a pale solid (yield ca. 80 percent). Itwas crystallized from acetone/n-hexane to give a purified product as themonohydrate (2.68 grams, 68 percent), M.P. 120-125 C.

Calcd. for C H NO -H O (percent): C, 64.10; H, 8.45; N, 6.24. Found(percent): C, 64.70; H, 8.67; N, 6.20.

EXAMPLE 3 2-amino-l-adamantaneacetamide A solution ofZ-keto-l-adamantaneacetamide monohydrate prepared as reported in Example2 (0.96 gram; 0.0046 mole) in ethanol (50 ml.) was heated to reflux andrefluxed for 30 minutes while ammonia gas was passed into the solution;the solution was then cooled to room temperature and saturated withammonia. After standing overnight the solution was hydrogenated over 10percent palladium on carbon for 24 hours at room temperature and 35lb./sq. in. pressure and for a further 6 hours at around 60 C. and 60lb./sq. in. The catalyst was filtered off, and the filtrate wasevaporated to dryness under vacuum. A solution of the residue inchloroform (10 ml.) was extracted with two 10 ml. portions of dilutehydrochloric acid. The bulked extract was basified and reextracted withtwo 10 ml. portions of chlorform and the chloroform extract was driedover magnesium sulfate and evaporated to give the desiredZ-aminO-I-adamantaneacetamide as a white solid (0.39 gram; 40 percent).It was crystallized from chloroform-light petroleum; the product soobtained was shown by melting point, mixed melting point and infraredspectrum procedures to be identical with a sample prepared fromZ-amino-l-adamantaneacetic acid (Examples 10, 11, and 12 hereinbelow).

EXAMPLE 4 5,7-diazatetracyclo(7.3.1.1 )tetradecan-6-one2-amino-1-adamantaneacetamide (3.3 grams; 0.0158 mole) Was added insmall portions to a stirred solution of bromine (0.95 ml., 0.019 mole)in 10 percent w./v. sodium hydroxide (40 ml.) at 0-5 C. After stirringfor 1 hour at 0-5 C., and 1 hour at 70-80" C., the solid was filtered01f, washed with water (20 ml.), dilute HCl (20 ml.) and water (20 ml.)again and crystallized from dimethylformamide to give5,7-diazatetracyclo(7.3.l.1 -0 )-tetradecan-6-one (1.83 grams; 56percent), M.P. 310-320" (dec.).

Calcd. for C H N O (percent): C, 69.86; H, 8.80; N, 13.58. Found(percent): C, 69.50; H, 8.84; N, 13.49.

EXAMPLE 2-keto-l-adamantanemethylamine 2-keto-l-adamantaneacetamideprepared as described in Example 2 (2.07 grams; 0.010 mole) was added insmall portions to a stirred solution of bromine (0.6 ml., 0.012 mole) in12 percent w./v. sodium hydroxide (20 ml.) at 0 C. The mixture wasstirred for 1% hours at 0 C., then 30 minutes at 70-80" C., cooled andextracted with ether (three ZO-milliliter portions). The extract waswashed with ml.), dried over magnesium sulfate, and treated withethanolic hydrochloric acid. The precipitate was crystallized fromethanol-ether to give 2-keto-1-adamantanemethylamine as thehydrochloride (1.2 grams; 56 per- Cent), M.P. 214220 C.

Calcd. for C H NO-HCl (percent): C, 61.25; H, 8.41; N, 6.50. Found(percent): C, 60.85; H, 8.33; N, 6.64.

EXAMPLE 6 Z-amino l-adamantanemethylamine Ammonia was passed into arefluxing solution of 2- keto-l-adamantanemethylamine hydrochloride(0.43 gram; 0.002 mole), prepared as reported in Example 5, in ethanol(25 ml.) for 30 minutes. After cooling and saturating with ammonia thesolution was hydrogenated at room temperature and atmospheric pressureover 10 percent palladium on carbon (0.1 gram) for 4 hours. The catalystwas filtered 01f and the filtrate was concentrated under vacuum,acidified with ethanolic HCl and diluted with ether to give 2-amino-l-adamantanemethylamine as the dihydrochloride (0.16 gram; 32percent), M.P. 300-310 C. (dec.).

Calcd. for C H N '2HCl (percent): C, 52.18; H, 8.76; N, 11.06. Found(percent): C, 52.10; H, 8.62; N, 10.60.

EXAMPLE 7 Z-keto-N-acetyl-l-adamantanemethylamine2-keto-l-adamantanemethylamine hydrochloride (0.50 gram; 0.0023 mole),prepared as described in Example 5, was dissolved in water (5 ml.), andthe solution was basified and extracted with chloroform (two5-milliliter portions). After drying over calcium sulfate, the extractwas treated with acetic anhydride (3 ml.) and heated under reflux for 1hour, then evaporated to dryness. The solid residue was washed withwater and crystallized from chloroform-light petroleum to give2-keto-N-acetyl-1- adamantanemethylamine 0.31 gram; 61 percent), M.P.122-124" C.

Calcd. for C H NO (percent): C, 70.55; H, 8.66; N, 6.33. Found(percent): C, 70.60; H, 9.10; N, 6.25.

EXAMPLE 8 1- acetamidomethyl -2-aminoadarnantane An ethanolic solutionof the Z-keto-N-acetyl-l-adamantanemethylamine prepared as reported inExample 7 was subjected to reductive amination with ammonia and hydrogenover 10 percent palladium on carbon at about 60 p.s.i. to giveZ-amino-N-acetyl-l-adamantanemethylamine, which upon dehydration yields6-methyl-5, 7-diazatetracyclo(7.3.1.1 .0 )tetradec-S-ene.

EXAMPLE 9 Z-methylamino-l-adarnantaneacetic acid A solution of2-lceto-1-admantaneacetic acid (6.24 grams; 0.030 mole) in a 33 percentw./v. solution of methylarnine in ethanol (150 ml.) was hydrogenated atatmospheric pressure over 10 percent palladium on charcoal (0.5 gram)for 6 hours. After removal of the catalyst the filtrate was evaporatedand the residue crystallized from ethanol-ether to give2-metyhlamino-1-admantaneacetic acid (6.8 grams; 100 percent), M.P.143-144 C.

Calcd. for C H NO (percent): C, 69.92; H, 9.48; N, 6.27. Found(percent): C, 70.40; H, 9.49; N, 6.55.

EXAMPLE 10 2-(benzyloxycarbonylamino)-1-adamantaneacetic acid Benzylchloroformate (4.1 grams; 0.024 mole) was added dropwise to a stirred,ice-cold solution of 2-aminol-adamantaneacetic acid hemihydrate (4.1grams; 0.021 mole) in 2 N sodium hydroxide (10 ml.), maintaining the pHat about 10-11 by addition of further 2 N sodium hydroxide (10 ml.),After stirring for a further 40 minutes at 0-5" C., the reaction mixturewas washed with ether (20 ml.), acidified with concentrated hydrochloricacid and extracted with ethyl acetate (three 25-milliliter portions).The extract was washed with water (10 ml.), dried over magnesiumsulfate, and evaporated to give, on addition of light petroleum,2-(benzyloxycarbonylamino)- l-adamantaneacetic acid (5.8 grams;percent), M.P. l34-135 C., recrystallized from acetone-hexane, MJP.136138 C.

Calcd. for C H NO (percent): C, 69.95; H, 7.34; N, 4.08. Found(percent): C, 70.25; H, 7.46; N, 4.17.

EXA'MPLE 11 Z-(benzyloxycarbonylamino)-1-admantaneacetarnide To astirred ice-cold solution ofZ-(benzyloxycarbonylamino)-l-adamantaneacetic acid (5.75 grams; 0.0168

mole) and triethylamine (2.44 ml., 0.0175 mole) in dry toluene (100 ml.)was added dropwise a solution of ethyl chloroformate (1.67 ml., 0.0175mole) in dry toluene (10 ml.). After stirring for 1 hour at C., thewhite solid was filtered off, ammonia was passed into the filtrate for 1hour, and the mixture was kept for 16 hours at room temperature. Thesolvent was removed under vacuum and a solution of the residue in ethylacetate (200 ml.) was washed successively with percent w./v. sodiumcarbonate (100 ml.) dilute hydrochloric acid (100 ml.), and water (50ml.) and crystallized by concentration and addition of light petroleumto give 2-(benzyloxycarbonylamino)- l-adamantaneacetamide (4.3 grams; 75percent), MJP. 160-163 C., recrystallized from acetone-hexane, M.P.166168 C.

Calcd. for C H N O (percent): C, 70.15; H, 7.65; N, 8.18. Found(percent): C, 70.80; H, 7.53; N, 8.15.

EXAMPLE 12 2-amino-1-adamantaneacetamide A solution of2-(benzyloxycarbonylamino) 1 adamantaneacetamide (5.4 grams; 0.0158mole) in ethanol (150 ml.) was hydrogenated at room temperature and 30lb./sq. in. pressure over percent palladium on carbon (1.0 gram) for 1hour. The catalyst was filtered oil and the filtrate evaporated to giveZ-amino-l-adamantaneacetamide (3.4 grams; 100 percent), M.P. 138-140 C.,recrystallized from chloroform-light petroleum, M.P. 156- 158 C.

Calcd. for C 'H N O (percent): C, 69.19; H, 9.68; N, 13.45. Found(percent): C, 69.10; H, 9.64; N, 13.20.

EXAMPLE 13 5,7-diazatetracyclo(7.3.1.1 .0)tetradecan-G-one2-amino-l-adamantaneacetamide, obtained as reported in Example 12, wasreacted in the same manner as described in Example 4 to obtain5,7-diazatetracyclo (7.3.l.1 .0 )tetradecan-6-one.

Other compounds representative of the present invention and prepared inaccordance with the foregoing teachings and examples include thefollowing.

EXAMPLES 14-17 0:,3,5,7-tetramethyl-2-keto-l-adamantaneacetic acid isconverted to a,3,5,7-tetramethyl-2-keto 1 adamantaneacetyl chloride,which in turn is converted to oc,3,5,7l6tl8.-methyl-Z-keto-l-adamantaneacetamide. Hoffmann degradation of this lastnamed compound yields a,3,5,7-tetramethyl-Z-keto-l-adamantanemethylaminewhich is reductively aminated with ammonia to yield a,3,5,7-tetramethyl-Z-amino-l-adamantanemethylamine.

EXAMPLES 1 8-2 1 a-n-Hexyl 5-isopropyl-2-keto-l-adamantaneacetic acid isconverted to a-n-hexyl 5-isopropyl-2-keto-l-adamantaneacetyl bromide,which in turn is converted to u-nhexyl5-isopropyl-2-keto-l-adamantaneacetamide. Holt mann degradation of thislast named compound yields an-hexyl 5 isopropylZ-keto-l-adamantanemethylamine which is reductively aminated withmethylamine to yielda-n-hexyl-5-isopropyl-2-methy1amino-l-adamantanemethylamine.

EXAMPLES 22-25 3,5 di-n-propyl-Z-keto-l-admantaneacetic acid isconverted to 3,5-di-n-propyl-2-keto-l-adamantaneacetyl chloride, whichin turn is converted to 3,5-di-n-propyl-2-ketol adamantaneacetamide.Hoffmann degradation of this last named compound yields 3,5 di-n-propyl2-keto-1- adamantanemethylamine which is reductively aminated withisopropylamine to yield 3,5-di-n-propyl-2-(isopropylamino)l-adamantanemethylamine.

EXAMPLES 26-29 u-n-Propyl-3,5,7-triethyl-2-keto-l-adamantaneacetic acid10 is converted to u-n-propyl 3,5,7-triethyl-2-keto-l-adamantaneacetylchloride, which in turn is converted to oc-H-propyl-3,5,7-triethyl-2-keto-l-adamantaneacetamide. Hofimann degradationof this last named compound yields an-propyl3,5,7-triethyl-2-keto-l-adamantanemethylamine which is reductivelyaminated with ethylamine to yield a-n-propyl3,5,7-triethy1-2-(ethylamino)-1-adamantanemethylamine.

EXAMPLES 30-32 a,3,5,7 tetramethyl-Z-keto-l-adamantanernethylamine isacylated by reaction with acetic anhydride to yield at, 3,5,7tetramethyl-2-keto-N-acetyl-l-admanantanemethylamine which in turn isreductively aminated with ammonia to obtain a,3,5,7-tetramethy1 2amino-N-acetyl-l-adamantanemethylamine. Cyclization of this last namedcompound yields 1,3,6,8,11 pentamethyl-5,7-diazatetracyclo- (7.3.1.1. .0)tetradec-5-ene.

EXAMPLES 33-35 a-n-Hexyl-S-isopropyl-Z-keto-l-adamantanemethylamine isacylated by reaction with propionic anhydride to yield a-n-hexyl5-isopropyl-2-keto-N-propionyl-l-adamantanemethylamine which in turn isreductively aminated with ammonia to obtainu-n-hexyl-5-isopropyl-Z-amino-N-propionyl-l-adamantanemethylamine.Cyclization of this last named compound yields8-n-hexyl-1-isopropyl-6-ethyl-5, 7ldiazatetracyclo(7.3.1.1 .0')tetradec-5-ene.

EXAMPLES 36-38 3,5 di-n-propyl 2-keto-l-adamantanemethylamino isacylated by reaction with butyric anhydride to yield 3,5- di-n-propyl2-keto-N-butyryl-l-adamantanemethylamine which in turn is reductivelyaminated with ammonia to obtain 3,5di-n-propyl-2-amino-N-butyryl-l-adamantanemethylamine. Cyclization ofthis last named compound yields 3,6,11tri-n-propyl-S,7-diazatetracyclo(7.3.1.l .0 ")tetradec-5-ene.

EXAMPLES 39-41 a-n-Propyl 3,5,7-triethyl-2-keto-l-adamantanemethylamineis acylated by reaction with acetic anhydride to yield a-n-propyl3,5,7-triethyl-2-keto-N-acetyl-l-adamantanemethylamine, which in turn isreductively aminated with ammonia to obtaina-n-propyl-3,5,7-triethyl-2-amino- N-acetyl l-adamantanemethylamine.Cyclization of this last named compound yields8-n-propyl-1,3,11-triethyl-6- methyl-5,7-diazatetracyclo(7.3.1.1 .0)tetradec-S-ene.

EXAMPLES 42-43 a,3,5,7 tetramethyl-Z-keto-l-adamantaneacetamide isreductively aminated by reaction with n-propylamine to yield oc,3,5,7tetramethyl-2-(n-propylamino)-l-adamantaneacetamide, which under Hoffmanrearrangement conditions cyclizes to 1,3,8,11tetramethyl-5-n-propy1-5,7- diazatetracyclo (7.3 1 1 .0)tetradecan-6-one.

EXAMPLES 44-46 EXAMPLES 47-483,5-di-n-propyl-2-keto-l-adamantaneacetamide is reducti-vely aminated byreaction with ammonia to yield 3,5-di-n-propyl-Z-amino-l-adamantaneacetamide, which under Hoifmanrearrangement conditions cyclizes to 1,3-di-npropyl 5,7diazatetracyclo(7.3.1.1 .0 )tetradecan-6- one.

EXAMPLES 49-51 a-n-Propyl-3,5,7-triethyl-2-keto-l-adamantaneacetic acidreductively aminated by reaction with methylamine to yield a-n-propyl3,5,7-triethyl-2-(methylaminoIi-l-adamantaneacetic acid, the amino groupof which is protected by reaction with benzyl chloroformate. Theamino-protected compound is then converted through the acetyl halide tothe amide and the amino-protecting group removed. As a result of theseoperations, there is obtainedu-n-propyl-3,5,7-triethyl-2-(methylamino)-l-adamantaneacetamide, whichunder Hoffman degradation conditions cyclizes to 8n-propyl-1,3,1l-triethyl--methyl-5,7-diazatetracyclo(7.3.1.1 .0)tetradecan-G-one.

The ultimate products of the present invention, compounds of Formulas Iand II, are useful as analgesics and as local anaesthetics inwarm-blooded animals. The compounds can be administered in any ofseveral routes, and can be formulated to facilitate administration, inliquid or solid formulations such as tablets, pills, capsules, granules,powders, oral solutions or suspensions, and the like. The exactconcentration of the present compound or compounds in the formulation isnot critical, it being necessary only that an appropriate dosage of thecompound or compounds be supplied to the animal being treated. Ingeneral, activity is obtained at rates of from 1 to 2.00 mg./ kg. ormore, depending upon the particular compound chosen, particular animaladministered to, mode of administration, and other factors. Suchadministration can be made on one occasion to relieve a particularsituation, or can be made on several occasions over a given period oftime, such as daily, to achieve a continuing therapeutic eifect. In arepresentative evaluation, a group of 5 mice was dosed,intraperitoneally in a carboxymethylcellulose suspension and at a rateof 100 mg./kg. Thirty minutes later the mice were challenged with 0.5percent acetic acid and observed for writhing normally resultant fromsuch challenge. Four mice of the treated group were completely protectedfrom writhing during the thirty minutes following administration. In acontrol group of 5 mice likewise challenged with 0.5 percent aceticacid, all exhibited writhing, there being a total of 85 writhes in thefirst 15 minutes following challenge and a total of 50 additionalwrithes in the next 15 minutes.

The starting materials to be employed in accordance with the presentinvention:

are prepared by oxidation of the corresponding2-hydroxyl-adamantaneethanol compounds:

In a representative oxidation, a solution of potassium permanganate (4.2grams; 0.027 mole) in 85 milliliters of water was added gradually to awell-stirred suspension of 2-hydroxy-1adamantaneethanol (3.0 grams;0.0143 mole) in 6.6 milliliters of a 10 percent aqueous solution ofsodium hydroxide. After the addition which was carried out at roomtemperature, a deep green color persisted, and another solution ofpotassium permanganate (4.2 grams; 0.027 mole, in milliliters of water)was added gradually. Thereafter, the reaction mixture was heated mildlyon a steambath for about 3 hours, after which it was permitted to cooland held overnight at room temperature. The reaction mixture was thenfiltered from manganese dioxide and the precipitate washed with water.The combined filtrate and wash were extracted with ether. The aqueouslayer was then acidified with dilute sulfuric acid, causingprecipitation of the desired 2-keto-1-adamantaneacetic acid product.This product was extracted with ether, and the resulting ether solutionwashed with water, dried over magnesium sulfate, and the solutionevaporated under subatmospheric pressure. The resulting product wascrystallized from a mixture of ether and nhexane to yield 2.5 grams ofZ-ketO-I-adamantaneacetic acid, M.P. -146 C.

Analysis.Calcd. (percent): C, 69.21; H, 7.75. Found (percent): C, 69.47;H, 7.83.

The product was converted in standard procedures to its oxime, M.P.153-155 C.

Analysis.-Calcd. (percent): C, 64.57; H, 7.65; N, 6.27. Found (percent):C, 65.10; H, 7.60; N, 6.10.

All of the Z-hydroxy-l-adamantaneethanol compounds are prepared in thesame manner described for the preparation ofZ-hydroxy-l-adamantaneethanol in pending U.S. application for LettersPatent Ser. No. 675,037, filed Oct. 13, 1967 now US. Pat. 3,591,642.

Thus, in these methods are prepared all of the starting materials to beused in accordance with the present invention. In respect to syntheticmethods concerning the adamantane structure, attention is also directedto a review of adamantane chemistry located in Chemical Reviews,

1964, pages 277-300, inclusive.

We claim:

1. The compound of the formula 1 ii R-Q-CH-C-halogen 2. The compound ofclaim 1 which is 2-keto-1-adamantaneacetyl chloride.

References Cited UNITED STATES PATENTS 3,468,950 9/1969 Chow et a1.260544 C X 3,591,642 7/1971 SZinai et a1. 26054'4 C X 3,644,356 2/ 1972Chakrabarti et a1.

260-544 C X 3,654,301 4/1971 Ch'akrabarti 260-514 G X LORRAINE A.WElNBERGER, Primary Examiner R. D. KELLY, Assistant Examiner

